Bottom line
This follow-up study (6 years after the original ADVANCE study) strengthens the findings of the first trial, namely that there is no mortality benefit to intensive blood sugar lowering for middle-aged patients with type 2 diabetes, while the addition of an angiotensin-converting enzyme inhibitor and diuretic reduces cardiovascular mortality and all-cause mortality. Intensive blood sugar control leads to a small reduction in end-stage renal disease, but at the price of more episodes of major hypoglycemia. (LOE = 1b)

Synopsis
The original ADVANCE trial randomized 11,140 adults 55 years or older with type 2 diabetes to receive perindopril 4 mg plus indapamide 1.25 mg and intensive blood sugar control (target glycated hemoglobin level < 6.5%), perindopril plus indapamide alone, intensive blood sugar control alone, or neither medications nor control. The median follow-up was 4.4 years, although the intensive blood sugar control part of the study continued for another 6 months, for a median follow-up of 5 years. After that, patients resumed usual care for their diabetes under the direction of their personal physician. Two years after the original trial ended, 80% of the trial sites agreed to participate in the follow-up ADVANCE-ON study reported here. The follow-up study included 8494 of the 10,261 living participants of the original trial, but the ADVANCE-ON participant’s characteristics were quite similar to those of the original group, and the treatment and placebo groups for both blood pressure medicine and intensive glucose monitoring comparisons remained balanced. At the first visit for the ADVANCE-ON study, the mean glycated hemoglobin level was 7.5% and the mean blood pressure was 143/80 for both groups. By the time of the first post-trial visit, the groups had converged regarding use of blood pressure medicines and the intensity of blood sugar control. By the end of the total 9.9-year follow-up period, there was a persistent mortality benefit for those originally assigned to perindopril plus indapamide (19.6% vs 21.1%; P = .03; number needed to treat [NNT] for 10 years = 67). The bulk of the benefit was due to a reduction in cardiovascular deaths. However, there was no difference in mortality between those in the intensive glucose control group and those in the usual control group (hazard ratio 1.0; 95% CI, 0.92 - 1.08). There was a reduction in the likelihood of end-stage renal disease in the intensive glucose control group (NNT = 200 for 10 years), but also an increase in the likelihood of major hypoglycemia (number needed to treat to harm = 77 for 10 years).

Bottom line
In patients with diabetes mellitus, angiotensin-converting enzyme inhibitors (ACEIs) decrease cardiovascular events and all-cause mortality. Angiotensin II receptor blockers (ARBs) don't. Both drug classes decrease heart failure incidence. Though both drug classes have been available for almost 15 years there is only one study of 250 patients that directly compared their effectiveness in patients with diabetes. So, we have to rely on this network analysis of studies that compared each drug class with other treatments. (LOE = 1a)

Synopsis
These Chinese researchers started their analysis by searching 3 databases, including the Cochrane Central Register of Controlled Trials, to identify randomized controlled studies comparing ACEIs and ARBs with no treatment, placebo, or active control treatment in patients with diabetes mellitus. They also searched a trial registry and meeting abstracts to find unpublished data. They identified 23 studies that evaluated ACEIs and 13 that tested ARBs. Only one study (enrolling just 250 patients) compared an ARB with an ACEI in this patient population. The quality of these studies is not great, so we have to be concerned about the validity of the data. ACEIs decreased all-cause mortality by 13% (95% CI, 2% - 22%), major cardiovascular events by 14% (5% - 33%), and heart failure by 19% (7% - 29%), and did not decrease stroke risk as compared with placebo or other treatments. ARBs did not affect any of these outcomes other than heart failure (30% decrease; 18% - 41%). Most (10/13) of the studies of ARBs used a placebo comparison group, which should have inflated their relative benefit.

Metformin Associated with Less Need for a Second Medicine

Clinical question
How well do oral hypoglycemics treat type 2 diabetes mellitus without the addition of a second treatment?

Bottom line
These results show that patients with type 2 diabetes whose treatment was started with an oral hypoglycemic other than metformin were significantly more likely to require a second oral agent. If prescribed a sulfonylurea, they were also more likely to experience a cardiovascular event over the following year; if prescribed a thiazolidinedione or dipeptidyl peptidase 4 inhibitor (gliptin), their out-of-pocket costs were significantly higher. Despite guideline recommendations and good evidence of benefit for metformin, more than 40% of newly diagnosed patients were not prescribed metformin. This study benefits from a large number of patients, but suffers from the possible biases inherent in all retrospective analyses. (LOE = 2b)

Synopsis
This study evaluated a dataset of one of the national health insurers in the United States. The researchers identified 15,516 patients who were started on a single oral hypoglycemic medicine. They analyzed subsequent prescriptions and hospitalizations for at least one year. Only 57.% of patients received metformin as their initial therapy, the medicine recommended by most guidelines based on clear evidence of benefit. About one-in-four patients initially receiving metformin were eventually prescribed a second oral medicine, which has significantly lower than those started on a sulfonylurea (37.1%), thiazolidinedione (39.6%), or a gliptin (36.2%). Patients started on a sulfonylurea were more likely than those started on other drugs to be subsequently started on insulin (9.1% vs 5.1% - 6.2%). Patients started on a sulfonylurea were more likely to experience a cardiovascular event or a diagnosis of hypoglycemia. Patients initially prescribed a thiazolidenidione or gliptin paid significantly more out-of-pocket.